Pharmaceutical hypocholesterolemic compositions

ABSTRACT

The present invention relates to novel azetidinone-containing compounds having a novel side-chain which is attached to the aryl ring at C4 via a C—C bond and comprises a 3,3-disubstituted oxetane ring and a polar group A, and which are useful in the treatment and prevention of atherosclerosis and for the reduction of cholesterol levels.

FIELD OF THE INVENTION

The present invention relates to novel oxetane-azetidinone derivatives and pharmaceutical compositions comprising said compounds alone or in combination with other active agents, methods of their production as well as their use in the treatment and prevention of atherosclerosis and for the reduction of cholesterol levels.

BACKGROUND

Atherosclerotic coronary heart disease represents the major cause for death and cardiovascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male gender, and cigarette smoke as well as serum cholesterol. Elevated concentrations of serum cholesterol have been demonstrated by a number of clinical studies to be a major contributing factor in the development and progression of atherosclerosis, which is characterized by the formation of cholesterol-containing plaques in the aorta and lesser arteries. In mammals, about ⅓ of the serum cholesterol is derived from exogenous dietary sources, which enters the body through absorption in the intestine, and ⅔ of the serum cholesterol are derived through endogenous de novo synthesis in the liver involving a complex set of enzyme-catalyzed reactions and regulatory mechanisms.

It has been reported in the literature that intestinal cholesterol absorption is an energy-independent, protein-mediated process rather than a passive diffusion process. Research efforts that focused on identifying classes of compounds that are able to interfere with the above-described processes have revealed that compound classes having a 2-azetidinone may be useful in lowering cholesterol and/or in inhibiting the formation of cholesterol-containing lesions in mammalian arterial walls.

A non-exhaustive list of such azetidinones can be found in WO 93/02048, WO 94/17038, WO 95/08532, WO 95/26334, U.S. Pat. No. 5,633,246, WO 95/35277, WO 96/16037, WO 96/19450, WO 97/16455, WO 02/50027, WO 02/50060, WO 02/50068, WO 02/50090, WO 02/66464, WO 04/000803, WO 04/000804, WO 04/000805, WO 04/081002, WO 05/021495, WO 05/021497, WO 05/033100, WO 05/044256, WO 05/044256, WO 05/062824, WO 05/061451, WO 05/061452, US 20040180860, US 20040180861, US 20050267049, U.S. Pat. No. RE 37,721, WO 2006/122186, WO 2006/137782, WO 2006/137792, WO 2006/137793, WO 2006/137794, WO 2006/137796, WO 2006/137797, WO 2007/015161, WO 2007/126358, WO 2008/052658, WO 2008/123953, WO 2008/085300, WO 2008/057336.

Extensive studies on the 2-azetidinones have shown that their activity was highly dependent on the nature and configuration of the various sidechains attached to the central β-lactam motif. These findings resulted in the development of the most prominent representative of the 2-azetidinones, Ezetimibe (also known under trade names Zetia™ and Ezetrol®), which is in use as a cholesterol-lowering drug in monotherapy and in dual therapy combined with a statin.

However, there are also side effects associated with this first generation of 2-azetidinones, which may include absorption and metabolization upon administration into the pharmalogically active glucuronide (van Heek, M. et al. Br. J. Pharmacol. 2000, 129, 1748-1754) as well as as allergic reactions, e.g. rash and angiodema. More recently a higher risk of developing cancer has been reported in specific cases.

Such drawbacks may be caused by e.g. the hydrolytic instability of the 2-azetidinone ring scaffold and/or the systemic nature of some of those compounds, which typically act as a prodrug and cause effective inhibition of the uptake of cholesterol in the small intestine only after absorption and metabolization into the pharmalogically active glucuronide (van Heek, M. et al. Br. J. Pharmacol. 2000, 129, 1748-1754).

Clearly, there is still a great need for effective inhibitors of dietary cholesterol transport or uptake through the gut membrane which show minimal drug-drug interactions and off-target pharmacology and thus have an improved safety/toxicology profile.

Applicants have now found that high pharmacological activity, i.e. inhibitory activity, can be achieved by linking the pharmacophore moiety of the molecule to a novel class of side-chains which confers beneficial toxicology and pharmacologic profile to the compounds of the invention. In particular, this side-chain intends to render the resulting bioconjugate poorly bioavailable and therefore may limit the risk caused by liver exposure. Thus, the compounds of the present invention with the structural characteristics as depicted hereinafter are able to inhibit cholesterol absorption, while overcoming the above described disadvantages of compounds known in the art.

SUMMARY OF THE INVENTION

The present invention relates to novel hypocholesterolemic compounds useful in the treatment and prevention of atherosclerosis and for the reduction of cholesterol levels as well as to pharmaceutical compositions comprising said compounds alone or in combination with other active agents.

In particular, the present invention relates to azetidinone compounds comprising a novel sidechain attached to C4-aryl of the β-lactam ring which is characterized by a C—C linkage to the lactams ring and the presence of an oxetane ring and a polar group.

Thus in a first aspect the present invention relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof,

wherein

-   W, X and Y represent, independently of each other, H,     —(C1-C10)alkyl, —OR₁, —NR₂R₃, -aryl, halogen, —CF₃, wherein R₁, R₂,     R₃ represent independently of each other H, (C1-10)alkyl or aryl; -   Z represents H, —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl,     aryl, or a polar group A selected from halogen, epoxy, —COR₆,     —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂R₁₃, phosphate groups,     phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides,     polyhydroxy, a 4- to 7-membered heteroaryl or heterocycloalkyl     having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈,     R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H,     (C1-C10)alkyl, aryl or heteroaryl, or combinations thereof such as     —(C1-C10)alkylaryl, —(C1-C10)alkenyl-aryl, —(C1-C10)alkynyl-aryl, or     one of —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, aryl     substituted by at least one polar group A; -   V represents —CH₂—, —CH(OH)—, —C(═O)—, —O—, NR₄, —C(CH₂OCH₂)—     wherein R₄ represents H, (C1-C10)alkyl or aryl; -   S is a sidechain of formula II

wherein the dotted line represents the linkage to the group of formula I;

-   B₁ represents (C1-C3)alkyl or —(CH₂)_(q)—NR₅—, wherein R₅ is H or     (C1-C6)alkyl, benzyl or aryl and q is 0, 1, 2, or 3; -   B₂ represents —C(O)NR^(d)—, —C(O)O—, aryl or heteroaryl; -   R^(a), R^(d) represent (i) independently of each other H,     (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from     halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁,     —CONR₁₂N₁₃, phosphate groups, phosphonate groups, sulfonate groups,     sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered     heteroaryl or heterocycloalkyl having 1 to 4 ring atoms selected     from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are     independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl,     or combinations thereof such as —(C1-C10)alkyl-aryl,     —(C1-C10)alkyl-cycloalkyl, or one of —(C1-C10)alkyl, cycloalkyl,     aryl substituted by at least one polar group A, or (ii) R^(a) and     R^(d) form together a N-containing 5- or 6-membered heteroaryl or     heterocycloalkyl; -   L₁, L₂ represent independently of each other a covalent bond, a 5-     or 6-membered arylgroup or a group —(CH₂)_(p)—, wherein p is 1, 2 or     3; -   R^(b), R^(c) represent (i) independently of each other H,     (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from     halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁,     —CONR₁₂N₁₃, phosphate groups, phosphonate groups, sulfonate groups,     sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered     heteroaryl or heterocycloalkyl having 1 to 4 ring atoms selected     from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are     independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl,     or combinations thereof such as —(C1-C10)alkyl-aryl,     —(C1-C10)alkylcycloalkyl, or one of —(C1-C10)alkyl, cycloalkyl, aryl     substituted by at least one polar group A, or (ii) R^(b) and R^(c)     form together a (C3-C6)cycloalkyl or (C3-6)heterocycloalkyl, -   m is 0, 1 or 2; -   n is 0 or 1;     with the proviso that at least one of groups R^(a), R^(b), R^(c),     R^(d) is a polar group A.

In a further aspect the invention is directed towards a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention with a pharmaceutically acceptable carrier, optionally in combination with one or more additional active agents.

In a further aspect the invention is directed towards the use of a compound or a pharmaceutical composition of the invention in the treatment or prevention of atheriosclerosis or for the reduction of cholesterol levels.

In yet a further aspect the invention is directed towards a kit comprising a pharmaceutical composition of the invention for the use in the treatment or prevention of artheriosclerosis or for the reduction of cholesterol levels.

In yet a further aspect the invention is directed towards a method for the treatment or prevention of artheriosclerosis or for the reduction of cholesterol levels comprising administering to a subject in need of such treatment an effective amount of a compound or a pharmaceutical composition of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel azetidinone-containing compounds having a novel side-chain which is attached to the aryl ring at C4 via a C—C bond and comprises a 3,3-disubstituted oxetane ring and a polar group A (hereinafter also called compounds of the invention), and which are useful in the treatment and prevention of atherosclerosis and for the reduction of cholesterol levels.

Unless stated otherwise, the following definitions apply:

The term “alkyl” or “(C1-10)alkyl” used alone or in combination with other groups should be understood to include straight chain and branched hydrocarbon groups having from 1 to 10, preferably 1 to 6, more preferably from 1 to 3 carbon atoms. Alkyl groups may be optionally substituted with one or more substituents. Non-limiting examples of suitable (C1-10)alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, fluoromethyl and trifluoromethyl.

The term “alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond. Alkenyl groups may be optionally substituted with one or more substituents.

The term “alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.

The optional substituents of alkyl, alkenyl and alkynyl groups may be the same or different, and are independently selected from H, (C1-10)alkyl, —OR″, —NR″R′″, —N⁺(R″)₂R′″, —OCOR″, —COOR″, —CONR″R′″, —CH═CHCOOR″, —CF₃, —CN, —NO₂, or halogen, wherein R″ and R′″ represent H or (C1-10)alkyl.

The term “branched” should be understood to represent a linear straight chain hydrocarbon group having one or more lower alkyl groups such as methyl, ethyl or propyl, attached to it.

The term “halogen” (or “hal”) should be understood to include fluoro, chloro, bromo, iodo, preferably fluoro and chloro, most preferably fluoro.

The term “polyhydroxy” refers to linear, cyclic or branched (C1-C10)alkyl chains being substituted by two to ten hydroxy groups at the same or different, preferably different C-atoms. In a preferred embodiment polydroxy groups may be characterized by the formula —(CH(OH))_(r)—, wherein r is 2 to 10, more preferably 2, 3, 4, 5 or 6.

The term “cycloalkyl” unless defined otherwise refers to a saturated monocyclic or bicyclic ring system having 3 to 10, preferably 3, 4, 5, 6 or 10, more preferably 3, 4, 5 or 6 ring atoms. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and the like.

The term “alkyl-cycloalkyl” (or “—(C1-C10)alkyl-cycloalkyl”) refers to a radical wherein alkyl (or (C1-10)alkyl) and cycloalkyl have the meanings as defined above. Illustrative examples of an alkyl-cycloalkyl group or radical include 3-methylcyclohexyl and 4-hexylcycloheptyl.

The term “heterocycloalkyl” unless defined otherwise refers to a cycloalkyl group as defined above, wherein one or more of the atoms in the ring system, preferably 1 to 3 is/are replaced by heteroatoms chosen from the group consisting of O, S, and N. Both uncharged as well as charged heteroaryls are included, thus for example “N” encompasses —NR_(x)—, wherein R_(x) is H or (C1-10)alkyl (uncharged heteroaryl) and —N⁺(R_(x))₂— where R_(x) is (C1-10)alkyl (charged heteroaryl). Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, oxazines, such as morpholine, thiazines and the like.

The term “aryl” unless defined otherwise should be understood to include a monocyclic or bicyclic, aromatic ring system having 5 to 10, preferably 5, 6 or 10, more preferably 5 or 6 ring atoms. Non-limiting examples of suitable aryl groups include phenyl, (1- or 2-)naphthyl or tetraline groups, most preferably phenyl groups.

The term “alkylaryl” (or “(C1-10)alkylaryl”) refers to a radical wherein alkyl (or (C1-10)alkyl) and aryl have the meanings as defined above. Illustrative examples of an alkylaryl group or radical include benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 3-methyl-3-phenylpropyl, 1-naphthylmethyl, 1-naphthylethyl.

The term “alkenylaryl” (or “(C1-10)alkenylaryl”) refers to a radical wherein alkenyl (or (C1-10)alkenyl) and aryl have the meanings as defined above. Particular examples of an alkenylaryl group or radical are vinyl benzene and -(3-(4-sulfonophenyl)prop-1-enyl).

The term “alkynylaryl” (or “(C1-10)alkynylaryl”) refers to a radical wherein alkynyl (or (C1-10)alkynyl) and aryl have the meanings as defined above. A particular example of an alkynylaryl group or radical is -(3-(4-sulfonophenyl)prop-1-ynyl).

The term “heteroaryl” unless defined otherwise should be understood to include an aromatic ring system of 5 to 10, preferably 5, 6 or 10, more preferably 5 or 6 ring atoms, in which one or more of the atoms in the ring system is/are atoms other than carbon, for example nitrogen, oxygen or sulfur. Preferably, the aromatic heteroaryl is a 5- or 6-membered aromatic ring having 1 to 3 heteroatoms selected from N, O, S, preferably N and O, and benzo-fused derivatives thereof. Examples of suitable 6-membered heteroaryl groups include pyridine, pyrimidine, pyrazine, pyridazine and the like. Examples of useful 5-membered aromatic heteroaryls include furan, pyrrole, triazole, thiazole, isothiazole, imidazole, pyrazole, oxazole and isoxazole. Useful bicyclic groups are benzo-fused ring systems derived from the aromatic heteroaryls named above, e.g., quinoline, phthalazine, quinazoline, benzofuran, phthaleimide and indole. Most preferred examples are pyridine, pyrimidine, oxazole, thiazole, imidazole, triazole, pyrazole, and phthaleimide.

The cyclic groups aryl, heteroaryl, cycloalkyl and heterocycloalkyl can be substituted with one or more substituents R′, preferably one, two or three substituents R′, which may be the same or different, and are independently selected from H, (C1-10)alkyl, —OR″, —NR″R′″, —N⁺(R″)₂R′″, —OCOR″, —COOR″, —CONR″R′″, —CH═CHCOOR″, —CF₃, —CN, —NO₂, or halogen, wherein R″ and R′″represent H or (C1-10)alkyl. Unless defined otherwise R′ represents preferably one or more substituents, preferably one, two or three substituents, selected from H, C1-10)alkyl, —OH, —O(C1-10)alkyl, —NR″R′″, —N⁺(R″)₂R′″, —CN, or halogen. For example, if R′ represents (C1-10)alkyl, alkylaryl groups such as benzyl, phenethyl and the like, alkylheteroaryl groups such as 2-furylmethyl, 2-thienylmethyl, 2-(1H-indol-3-yl)ethyl and the like, alkylcycloalkyl groups such as cyclohexylmethyl, cyclopentylpropyl, and the like, and alkylheterocycloalkyl groups such as 2-(1-pyrrolidinyl)ethyl, 4-morpholinylmethyl, (1-methyl-4-piperidinyl)methyl and the like, are included. Charged alkylheterocycloalkyls are included as well, for example when the (C1-10)alkyl group is attached to e.g. an N-ring atom. The substituents R′ may be in any position.

For example in monosubstituted phenyl residues the substituent can be located in the ortho-position, the meta-position or the para-position, preferably in the para-position. If phenyl is substituted twice, the substituents can be in the ortho/meta-position (all possibilities), the ortho/para-position, the ortho/ortho-position, the meta/meta-position, or the meta/para-position. In substituted heteroaryl or heterocycloalkyl groups, the substituent may reside on a carbon atom or a heteroatom, such that charged groups are contemplated as well, e.g. N-methyl morpholinium and the like.

The term “polar group” should be understood to include any polar moiety which enhances and thus imparts impermeability to the compounds of the invention. This includes uncharged and charged (both positively and negatively) groups. Typical examples of such moieties include halogen, carbonyl groups including carboxylic acids and carboxylic amides, amine and amino acid residues, glucuronides, polyhydroxy groups and glucamine derivatives, 2,3-dihydroxy propoxy groups, tartrate groups, N-(2-Hydroxyethyl)-iminodiacetic acid groups, heteroaryl groups (e.g. pyridine, oxazole, isoxazole, triazole and tetrazolium (salt) groups), phosphate groups, phosphonate groups, sulfate groups (e.g. R—O—SO₃— and R₂N—SO₃-groups), sulfonate groups R—SO₂—O—R (which include e.g. sulfonic acid, sulfonic salts and sulfonic esters), sulfonyl groups R—SO₂₋R, which include e.g. sulfonamides —RN—SO₂— (such as —NR₁₄SO₂R₁₅ or —SO₂NR₁₆R₁₇, wherein R₁₄, R₁₅, R₁₆, R₁₇ are independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl), isomers of salicylic acid (all combinations of disubstituted phenyl with OH and COOH substituents), alkylamine groups —NR₈R₉, alkylammonium or arylammonium groups —N⁺R₈R₉R₁₀ and the corresponding quaternary ammonium salts and derivatives thereof. Preferred groups include carboxylic acid groups, aminoacid residues, polyhydroxy groups, tartrate groups, N-(2-Hydroxyethyl)-iminodiacetic acid groups, phosphate or phosphonate groups, sulfate, sulfonate, sulfonyl or sulfonamide groups, alkylamine groups, alkylammonium or arylammonium groups, and derivatives thereof, more preferably carboxylic acid groups, aminoacid residues, phosphonate groups, sulfonates, sulfonyl or sulfonamide groups, alkylammonium groups and derivatives thereof.

The term “alkylammonium” as used herein encompasses mono-, di- and tri-alkyl ammonium groups wherein alkyl groups contain from 1 to 10 carbon atoms and are either in non-cyclic form (i.e. single chains) or form together with the N-group an N-containing heterocycle, as well as cycloalkyl groups containing from 3 to 6 carbon atoms. The alkylammonium group includes, for example, mono-, di- and tri-methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, t-butyl, t-pentyl ammonium groups, cyclopropyl ammonium, cyclobutylethylammonium, cyclopentylmethyl ammonium, cyclohexylammonium, as well as a quaternary ammonium group of e.g. piperazine, morpholine, piperidine and the like.

The term “arylammonium” as used herein encompasses preferably a cationic derivative of an aryl-substituted amine or an aryl-bonded amine. Examples for an aryl-substituted amine (or ammonium) includes e.g. aniline and substituted anilines such as the mono-, di- and tri-halo, nitro, methoxy, methyl, and ethyl anilines (or unsubstituted or substituted phenylammonium), and specifically cationic derivatives derived from the primary phenyl amines such as aniline, methoxyaniline, ethoxyaniline, o,m,p-toluidine, o,m,p-chloroaniline, o,m,p-anisidine, o, m, and p-nitroaniline, 2,4-dichloroaniline, 3,5-dichloroaniline, 2,5-diiodoaniline, o, m, and p-bromoaniline and the like. Examples of a cationic derivative of an aryl-bonded amine include an ammonium group of e.g. imidazole, pyridine, pyrimidine, pyrazole, chinoline, and the like.

A skilled person will know that, if the polar moiety is a positively charged group, a suitable counterion will be derived from an organic or inorganic acid. Such counterions include halide (such as chloride, bromide, fluoride, iodide), sulfate, phosphate, acetate, succinate, citrate, lactate, maleate, fumarate, palmitate, cholate, glutamate, glutarate, tartrate, stearate, salicylate, methanesulfonate, benzenesulfonate, sorbate, picrate, benzoate, cinnamate, and the like. If the polar moiety is a negatively charged groups, a suitable counterion will be selected from sodium, ammonium, barium, calcium, copper, iron, lithium, potassium and zinc, and the like.

In one embodiment the polar group is a polar group A selected from halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂N₁₃, phosphate groups, phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered heteroaryl or heterocycloalkyl having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H, (C1-C10)alkyl, aryl or heteroaryl.

For any one of groups R^(a), R^(b), R^(c) and R^(d) group A may represent group A1 selected from —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂N₁₃, polyhydroxy, sulfonate group, sulfonamides (such as NR₁₄SO₂R₁₅ or —SO₂NR₁₆R₁₇), phosphonate group, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl groups or a combination thereof such as -piperazine-SO₃H, —N(CH₂CH₂)₂N⁺R₁₄R₁₅, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇ are independently of each other H or (C1-C10)alkyl.

For group Z group A may preferably represent a group A2 selected from halogen, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂R₁₃, —SO₃H, —NR₁₄SO₂R₁₅, —SO₂NR₁₆R₁₇, —SO₂R₁₈, polyhydroxy, heteroaryl, or heterocycloalkyl, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈ are independently of each other H, —(C1-C10)alkyl, aryl or heteroaryl, and wherein the heteroaryl is selected from pyridine, pyrimidine, oxazole, thiazole, imidazole, triazole, pyrazole, and phthaleimide.

Thus, preferred combinations of group Z (represented by “—(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, aryl substituted by at least one polar group A”) include —(C1-C10)alkyl-COR₆, —(C1-C10)alkenyl-COR₆, —(C1-C10)alkynyl-COR₆, —(C1-C10)alkyl-COOR₇, —(C1-C10)alkenyl-COOR₇, —(C1-C10)alkynyl-COOR₇, —(C1-C10)alkyl-NR₈R₉, —(C1-C10)alkenyl-NR₈R₉, —(C1-C10)alkynyl-NR₈R₉, —(C1-C10)alkyl-N⁺R₈R₉R₁₀, —(C1-C10)alkenyl-N⁺R₈R₉R₁₀, —(C1-C10)alkynyl-N⁺R₈R₉R₁₀, —(C1-C10)alkyl-OR₁₁, —(C1-C10)alkenyl-OR₁₁, —(C1-C10)alkynyl-OR₁₁, —(C1-C10)alkyl-CONR₁₂N₁₃, —(C1-C10)alkenyl-CONR₁₂N₁₃, —(C1-C10)alkynyl-CONR₁₂N₁₃, —(C1-C10)alkyl-SO₃H, —(C1-C10)alkenyl-SO₃H, —(C1-C10)alkynyl-SO₃H, —(C1-C10)alkyl-SO₂R₁₈, —(C1-C10)alkenyl-SO₂R₁₈, —(C1-C10)alkynyl-SO₂R₁₈, —(C1-C10)alkyl SO₂NR₁₆R₁₇, —(C1-C10)alkenyl-SO₂NR₁₆R₁₇, —(C1-C10)alkynyl-SO₂NR₁₆R₁₇, —(C1-C10)alkyl-NR₁₄SO₂R₁₅, —(C1-C10)alkenyl-NR₁₄SO₂R₁₅, —(C1-C10)alkynyl-NR₁₄SO₂R₁₅, —(C1-10)alkyl-heteroaryl, —(C1-C10)alkenyl-heteroaryl, —(C1-C10)alkynyl-heteroaryl, —(C1-10)alkyl-heterocycloalkyl, —(C1-C10)alkenyl-heterocycloalkyl, —(C1-C10)alkynyl-heterocycloalkyl wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈ are independently of each other H, —(C1-C10)alkyl, aryl or heteroaryl, and wherein the heteroaryl is selected from pyridine, pyrimidine, oxazole, thiazole, imidazole, triazole, pyrazole, and phthaleimide.

More preferred combinations of group Z (represented by “—(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, aryl substituted by at least one polar group A”) include, —(C1-C10)alkyl-COOR₇, —(C1-C10)alkenyl-COOR₇, —(C1-C10)alkynyl-COOR₇, —(C1-C10)alkyl-NR₈R₉, —(C1-C10)alkenyl-NR₈R₉, —(C1-C10)alkynyl-NR₈R₉, —(C1-C10)alkyl-N⁺R₈R₉R₁₀, —(C1-C10)alkenyl-N⁺R₈R₉R₁₀, —(C1-C10)alkynyl-N⁺R₈R₉R₁₀, —(C1-C10)alkyl-OR₁₁, —(C1-C10)alkenyl-OR₁₁, —(C1-C10)alkynyl-OR₁₁, —(C1-C10)alkyl-SO₃H, —(C1-C10)alkenyl-SO₃H, —(C1-C10)alkynyl-SO₃H, —(C1-C10)alkyl-SO₂R₁₈, —(C1-C10)alkenyl-SO₂R₁₈, —(C1-C10)alkynyl-SO₂R₁₈, —(C1-C10)alkyl-SO₂NR₁₆R₁₇, —(C1-C10)alkenyl-SO₂NR₁₆R₁₇, —(C1-C10)alkynyl-SO₂NR₁₆R₁₇, —(C1-C10)alkyl-NR₁₄SO₂R₁₅, —(C1-C10)alkenyl-NR₁₄SO₂R₁₅, —(C1-C10)alkynyl-NR₁₄SO₂R₁₅, wherein R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈ are independently of each other H, —(C1-C10)alkyl, aryl or heteroaryl, and wherein the heteroaryl is selected from pyridine, pyrimidine, oxazole, thiazole, imidazole, triazole and pyrazole.

It is further understood that all isomers, including enantiomers, stereoisomers, rotamers, tautomers and racemates of the compounds of formula I are contemplated as being part of this invention. The invention includes stereoisomers in optically pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of formula I. In a preferred embodiment the stereochemistry in the central ring is such that the substituents at the 3- and 4-position are in trans configuration to each other.

More specifically, the present invention relates to a compound according to formula I or a pharmaceutically acceptable salt or solvate thereof,

wherein

-   W, X and Y represent, independently of each other, H,     —(C1-C10)alkyl, —OH, —O(C1-C10)alkyl, -aryl, halogen, —CF₃; -   Z represents H, —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl,     aryl, or a polar group A selected from halogen, epoxy, —COR₆,     —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂N₁₃, phosphate groups,     phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides,     polyhydroxy, a 4- to 7-membered heteroaryl or heterocycloalkyl     having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈,     R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H,     (C1-C10)alkyl, aryl, or heteroaryl, or combinations thereof such as     —(C1-C10)alkyl-aryl, —(C1-C10)alkenyl-aryl, —(C1-C10)alkynyl-aryl,     or one of —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, aryl     substituted by at least one polar group A; -   V represents —CH₂—, —CH(OH)—, —C(═O)—, —O—, NR₄, —C(CH₂OCH₂)—     wherein R₄ represents H, (C1-C10)alkyl or aryl; -   S is a sidechain of formula II

wherein the dotted line represents the linkage to the group of formula I;

-   B₁ represents (C1-C3)alkyl or —(CH₂)_(q)—NR₅—, wherein R₅ is H or     (C1-C6)alkyl, benzyl or aryl and q is 0, 1, 2, or 3; -   B₂ represents —C(O)NR^(d)—, —C(O)O—, aryl or heteroaryl; -   R^(a), R^(d) represent (i) independently of each other H,     (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from     halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁,     —CONR₁₂N₁₃, phosphate groups, phosphonate groups, sulfonate groups,     sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered     heteroaryl or heterocycloalkyl having 1 to 4 ring atoms selected     from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are     independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl,     or combinations thereof such as —(C1-C10)alkyl-aryl,     —(C1-C10)alkylcycloalkyl, or one of —(C1-C10)alkyl, cycloalkyl, aryl     substituted by at least one polar group A, or (ii) R^(a) and R^(d)     form together a N-containing 5- or 6-membered heteroaryl or     heterocycloalkyl; -   L₁, L₂ represent independently of each other a covalent bond, a 5-     or 6-membered arylgroup or a group —(CH₂)_(p)—, wherein p is 1, 2 or     3; -   R^(b), R^(c) represent (i) independently of each other H,     (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from     halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁,     —CONR₁₂N₁₃, phosphate groups, phosphonate groups, sulfonate groups,     sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered     heteroaryl or heterocycloalkyl having 1 to 4 ring atoms selected     from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are     independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl,     or combinations thereof such as —(C1-C10)alkyl-aryl,     —(C1-C10)alkylcycloalkyl, or one of —(C1-C10)alkyl, cycloalkyl, aryl     substituted by at least one polar group A, or (ii) R^(b) and R^(c)     form together a (C3-C6)cycloalkyl or (C3-6)heterocycloalkyl, -   m is 0, 1 or 2; -   n is 0 or 1;     with the proviso that at least one of groups R^(a), R^(b), R^(c),     R^(d) is a polar group A.

It is understood that R^(a) and R^(d) may only form together a N-containing 5- or 6-membered heteroaryl or heterocycloalkyl if B₂ equals —C(O)NR^(d)—.

In a specific embodiment the polar group A in groups R^(a) and R^(d) is a polar group A1 selected from —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂N₁₃, polyhydroxy, sulfonate group, sulfonamides (such as NR₁₄SO₂R₁₅ or —SO₂NR₁₆R₁₇), phosphonate group, piperazinyl, piperidinyl, pyrrolidinyl, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇ are independently of each other H or (C1-C10)alkyl.

As indicated above, one polar group has to be present in either R^(a), R^(b), R^(c), R^(d) of the side chain S. Thus, in one embodiment, R^(b) and R^(c) are independently of each other H, (C1-C10)alkyl, aryl, cycloalkyl, aryl, heteroaryl or form together a (C3-C6)cycloalkyl or (C3-6)heterocycloalkyl and R^(d) is H, (C1-C10)alkyl, cycloalkyl, aryl, heteroaryl; and R^(a) represents a polar group A, preferably a polar group A1.

In another embodiment R^(a) and R^(d) form together a N-containing 5- or 6-membered heteroaryl or heterocycloalkyl; and R^(b) and R^(c) represent independently of each other H, (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A or combinations thereof such as —(C1-C10)alkyl-aryl, —(C1-C10)alkyl-cycloalkyl, or one of —(C1-C10)alkyl, cycloalkyl, aryl substituted by at least one polar group A, preferably a polar group A1, with the proviso that at least one R^(b) and R^(c) comprises a polar group A, preferably a polar group A1. It is understood that for m=2 all four substituents R^(b) and R^(c) can be selected independently of each other. Preferred N-containing 5- or 6-membered heteroaryl or heterocycloalkyl include unsubstituted or substituted pyridine, pyrimidine, imidazole, triazole, pyrazole, pyrrolidine, piperidine.

In yet another embodiment R^(b), R^(c), R^(d) are independently of each other H, (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A and combinations thereof such as —(C1-C10)alkyl-aryl, —(C1-C10)alkyl-cycloalkyl, or one of —(C1-C10)alkyl, cycloalkyl, aryl substituted by at least one polar group A, preferably a polar group A1 and R^(a) is a polar group A, preferably a polar group A1.

In yet other embodiments either two or three or all of groups R^(a), R^(b), R^(c), R^(d) are a polar group A, preferably a polar group A1.

Z represents preferably H, —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, aryl, or a polar group A2 selected from halogen, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂R₁₃, —SO₃H, —NR₁₄SO₂R₁₅, —SO₂NR₁₆R₁₇, —SO₂R₁₈, polyhydroxy, heteroaryl, or heterocycloalkyl, or combinations thereof such as —(C1-C10)alkyl-aryl, —(C1-C10)alkenyl-aryl, —(C1-C10)alkynyl-aryl, —(C1-C10)alkyl COR₆, —(C1-C10)alkenyl-COR₆, —(C1-C10)alkynyl-COR₆, —(C1-C10)alkyl-COOR₇, —(C1-C10)alkenyl-COOR₇, —(C1-C10)alkynyl-COOR₇, —(C1-C10)alkyl-NR₈R₉, —(C1-C10)alkenyl-NR₈R₉, —(C1-C10)alkynyl-NR₈R₉, —(C1-C10)alkyl-N⁺R₈R₉R₁₀, —(C1-C10)alkenyl-N⁺R₈R₉R₁₀, —(C1-C10)alkynyl-N⁺R₈R₉R₁₀, —(C1-C10)alkyl-OR₁₁, —(C1-C10)alkenyl-OR₁₁, —(C1-C10)alkynyl-OR₁₁, —(C1-C10)alkyl-CONR₁₂N₁₃, —(C1-C10)alkenyl-CONR₁₂N₁₃, —(C1-C10)alkynyl-CONR₁₂N₁₃, —(C1-C10)alkyl-SO₃H, —(C1-C10)alkenyl-SO₃H, —(C1-C10)alkynyl-SO₃H, —(C1-C10)alkyl-SO₂R₁₈, —(C1-C10)alkenyl-SO₂R₁₈, —(C1-C10)alkynyl-SO₂R₁₈, —(C1-C10)alkyl-SO₂NR₁₆R₁₇, —(C1-C10)alkenyl-SO₂NR₁₆R₁₇, —(C1-C10)alkynyl-SO₂NR₁₆R₁₇, —(C1-C10)alkyl-NR₁₄SO₂R₁₅, —(C1-C10)alkenyl-NR₁₄SO₂R₁₅, —(C1-C10)alkynyl-NR₁₄SO₂R₁₅, —(C1-10)alkyl-heteroaryl, —(C1-C10)alkenyl-heteroaryl, —(C1-C10)alkynyl-heteroaryl, —(C1-10)alkyl-heterocycloalkyl, —(C1-C10)alkenyl-heterocycloalkyl, —(C1-C10)alkynyl-heterocycloalkyl wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈ are independently of each other H, —(C1-C10)alkyl, aryl or heteroaryl, and wherein the heteroaryl is selected from pyridine, pyrimidine, oxazole, thiazole, imidazole, triazole, pyrazole, and phthaleimide.

More preferably Z represents H, —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, aryl, or a polar group A2 selected from halogen, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂R₁₃, —SO₃H, —NR₁₄SO₂R₁₅, —SO₂NR₁₆R₁₇, —SO₂R₁₈, polyhydroxy, heteroaryl, or heterocycloalkyl, or combinations thereof such as —(C1-C10)alkyl-aryl, —(C1-C10)alkenyl-aryl, —(C1-C10)alkynyl aryl, —(C1-C10)alkyl-COOR₇, —(C1-C10)alkenyl-COOR₇, —(C1-C10)alkynyl-COOR₇, —(C1-C10)alkyl-NR₈R₉, —(C1-C10)alkenyl-NR₈R₉, (C1-C10)alkynyl-NR₈R₉, —(C1-C10)alkyl-N⁺R₈R₉R₁₀, —(C1-C10)alkenyl-N⁺R₈R₉R₁₀, —(C1-C10)alkynyl-N⁺R₈R₉R₁₀, —(C1-C10)alkyl-OR₁₁, —(C1-C10)alkenyl-OR₁₁, —(C1-C10)alkynyl-OR₁₁, —(C1-C10)alkyl-SO₃H, —(C1-C10)alkenyl-SO₃H, —(C1-C10)alkynyl-SO₃H, —(C1-C10)alkyl-SO₂R₁₈, —(C1-C10)alkenyl-SO₂R₁₈, —(C1-C10)alkynyl-SO₂R₁₈, —(C1-C10)alkyl-SO₂NR₁₆R₁₇, —(C1-C10)alkenyl-SO₂NR₁₆R₁₇, —(C1-C10)alkynyl-SO₂NR₁₆R₁₇, —(C1-C10)alkyl-NR₁₄SO₂R₁₅, —(C1-C10)alkenyl-NR₁₄SO₂R₁₅, —(C1-C10)alkynyl-NR₁₄SO₂R₁₅, wherein R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈ are independently of each other H, —(C1-C10)alkyl, aryl or heteroaryl, and wherein the heteroaryl is selected from pyridine, pyrimidine, oxazole, thiazole, imidazole, triazole and pyrazole.

B₁ represents preferably —CH₂— or —CH₂—CH₂—NR₅—, wherein R₅ is H, (C1-C6)alkyl, benzyl or aryl.

In one embodiment B₁ represents —CH₂— and n=1. In another embodiment B₁ represents —CH₂—CH₂—NR₅—, wherein R₅ is H, (C1-C6)alkyl, benzyl or aryl and n=0.

B₂ represents preferably —C(O)NR^(d)—, —C(O)O—, or a five-membered heteroaryl having two heteroatoms selected from N, O, such as oxazole, thiazole, imidazole.

In preferred embodiments L₁ is —(CH₂)_(p)—, wherein p is 1, 2 or 3 and L₂ is a covalent bond, or (ii) L₁ is a covalent bond and L₂ is a 5- or 6-membered arylgroup.

In a further embodiment, the side chain containing the oxetane ring is placed at the para position of the benzene ring attached at C4 of the β-lactam.

In one embodiment Z is H and Y is —F in para position.

In another embodiment Z is a polar group A, preferably a polar group A2 and Y is —F in para position.

V is preferably CH(OH), —C(═O)— or —O— and/or wherein W, X, Y and Z independently represent H, halogen, or —OH.

In a specific embodiment S is a group of formula IIIa or IIIb

wherein

-   B₂ represents —C(O)NR^(d)—, —C(O)O—, aryl or heteroaryl; -   R^(a), R^(d) represent (i) independently of each other H,     (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from     halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁,     —CONR₁₂N₁₃, phosphate groups, phosphonate groups, sulfonate groups,     sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered     heteroaryl or heterocycloalkyl having 1 to 4 ring atoms selected     from N, O, S, wherein R₈, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are     independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl,     or combinations thereof such as —(C1-C10)alkyl-aryl,     —(C1-C10)alkylcycloalkyl, or one of —(C1-C10)alkyl, cycloalkyl, aryl     substituted by at least one polar group A, or (ii) R^(a) and R^(d)     form together a N-containing 5- or 6-membered heteroaryl or     heterocycloalkyl; -   L₁, L₂ represent independently of each other a covalent bond, a 5-     or 6-membered arylgroup or a group —(CH₂)_(p)—, wherein p is 1, 2 or     3; -   R^(b), R^(c) represent (i) independently of each other H,     (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from     halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁,     —CONR₁₂N₁₃, phosphate groups, phosphonate groups, sulfonate groups,     sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered     heteroaryl or heterocycloalkyl having 1 to 4 ring atoms selected     from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are     independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl,     or combinations thereof such as —(C1-C10)alkyl-aryl,     —(C1-C10)alkylcycloalkyl, or one of —(C1-C10)alkyl, cycloalkyl, aryl     substituted by at least one polar group A, or (ii) R^(b) and R^(c)     form together a (C3-C6)cycloalkyl or (C3-6)heterocycloalkyl, -   m is 0, 1 or 2;     with the proviso that at least one of groups R^(a), R^(b), R^(c),     R^(d) is a polar group A. -   B₂ represents preferably —C(O)NR^(d)—, —C(O)O—, or a five-membered     heteroaryl having two heteroatoms selected from N, O, such as     oxazole, thiazole, imidazole.

The at least one of groups R^(a), R^(b), R^(c), R^(d) is preferably a polar group A1.

In preferred embodiments L₁ is —(CH₂)_(p)—, wherein p is 1, 2 or 3 and L₂ is a covalent bond, or (ii) L₁ is a covalent bond and L₂ is a 5- or 6-membered arylgroup.

In a further specific embodiment S is a group of formula IVa, IVb, IVc or formula Va, Vb, Vc

wherein

-   Q is —O—, —NR₅—, —S—, -   L₁, L₂ represent independently of each other a covalent bond, a 5-     or 6-membered arylgroup or a group —(CH₂)_(p)—, wherein p is 1, 2 or     3; -   R₅ is H, (C1-C6)alkyl, benzyl or aryl; -   m is 0, 1 or 2; -   R^(a), R^(d) represent independently of each other H, (C1-C10)alkyl,     cycloalkyl, aryl, or a polar group A selected from halogen, epoxy,     —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂N₁₃, phosphate     groups, phosphonate groups, sulfonate groups, sulfonyl groups,     sulfonamides, polyhydroxy, a 4- to 7-membered heteroaryl or     heterocycloalkyl having 1 to 4 ring atoms selected from N, O, S,     wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each     other H, (C1-C10)alkyl, aryl, or heteroaryl, or combinations thereof     such as —(C1-C10)alkylaryl, —(C1-C10)alkyl-cycloalkyl, or one of     —(C1-C10)alkyl, cycloalkyl, aryl substituted by at least one polar     group A, or R^(a) and R^(d) form together a N-containing 5- or     6-membered heteroaryl or heterocycloalkyl; -   R^(b), R^(c) represent (i) independently of each other H,     (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from     halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁,     —CONR₁₂N₁₃, phosphate groups, phosphonate groups, sulfonate groups,     sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered     heteroaryl or heterocycloalkyl having 1 to 4 ring atoms selected     from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are     independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl,     or combinations thereof such as —(C1-C10)alkyl-aryl,     —(C1-C10)alkyl-cycloalkyl, or one of —(C1-C10)alkyl, cycloalkyl,     aryl substituted by at least one polar group A, or (ii) R^(b) and     R^(c) form together a (C3-C6)cycloalkyl or (C3-6)heterocycloalkyl;     with the proviso that at least one of groups R^(a), R^(b), R^(c),     R^(d) is a polar group A.

The at least one of groups R^(a), R^(b), R^(c), R^(d) is preferably a polar group A1.

In a specific embodiment the present invention relates to compounds of the present invention having formula VIa, VIb, VIc or formula VIIIa, VIIb, VIIc or a pharmaceutically acceptable salt thereof,

wherein

-   X, Y are, independently of each other, H, OH or F; -   Z represents H, —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl,     aryl, or a polar group A selected from halogen, epoxy, —COR₆,     —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂N₁₃, phosphate groups,     phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides,     polyhydroxy, a 4- to 7-membered heteroaryl or heterocycloalkyl     having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈,     R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H,     (C1-C10)alkyl, aryl, or heteroaryl, or combinations thereof such as     —(C1-C10)alkylaryl, —(C1-C10)alkenyl-aryl, —(C1-C10)alkynyl-aryl, or     one of —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, aryl     substituted by at least one polar group A; -   Q is —O—, —NR₅—, —S—, -   m is 0, 1 or 2; -   L₁, L₂ represent independently of each other a covalent bond, a 5-     or 6-membered arylgroup or a group —(CH₂)_(p)—, wherein p is 1, 2 or     3; -   R₅ is H, (C1-C6)alkyl, benzyl or aryl; -   R^(a), R^(d) represent independently of each other (i) H,     (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from     halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁,     —CONR₁₂N₁₃, phosphate groups, phosphonate groups, sulfonate groups,     sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered     heteroaryl or heterocycloalkyl having 1 to 4 ring atoms selected     from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are     independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl,     or combinations thereof such as —(C1-C10)alkyl-aryl,     —(C1-C10)alkyl-cycloalkyl, or one of —(C1-C10)alkyl, cycloalkyl,     aryl substituted by at least one polar group A, or (ii) R^(a) and     R^(d) form together a N-containing 5- or 6-membered heteroaryl or     heterocycloalkyl; -   R^(b), R^(c) represent (i) independently of each other H,     (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from     halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁,     —CONR₁₂N₁₃, phosphate groups, phosphonate groups, sulfonate groups,     sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered     heteroaryl or heterocycloalkyl having 1 to 4 ring atoms selected     from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R¹³ are     independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl,     or combinations thereof such as —(C1-C10)alkyl-aryl,     —(C1-C10)alkyl-cycloalkyl, or one of —(C1-C10)alkyl, cycloalkyl,     aryl substituted by at least one polar group A, or (ii) R^(b) and     R^(c) form together a (C3-C6)cycloalkyl or (C3-6)heterocycloalkyl;     with the proviso that at least one of groups R^(a), R^(b), R^(c),     R^(d) is a polar group A.

In preferred embodiments L₁ is —(CH₂)_(p)—, wherein p is 1, 2 or 3 and L₂ is a covalent bond, or (ii) L₁ is a covalent bond and L₂ is a 5- or 6-membered arylgroup.

In one embodiment Z is H and Y is preferably —F in para position.

In another embodiment the at least one of groups R^(a), R^(b), R^(c), R^(d) is a polar group A1.

In yet another embodiment Z is a polar group A, preferably a polar group A2, and Y is preferably —H or —F.

In yet further preferred embodiments the invention is directed towards compounds of formula VIIIa or VIIIb

wherein

-   X, Y are independently of each other, H, OH or F; -   Z represents H, —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl,     aryl, or a polar group A selected from halogen, epoxy, —COR₆,     —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂N₁₃, phosphate groups,     phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides,     polyhydroxy, a 4- to 7-membered heteroaryl or heterocycloalkyl     having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈,     R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H,     (C1-C10)alkyl, aryl or heteroaryl, or combinations thereof such as     —(C1-C10)alkyl-aryl, —(C1-C10)alkenyl-aryl, —(C1-C10)alkynyl-aryl,     or one of —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, aryl     substituted by at least one polar group A; -   R^(b), R^(c) represent independently of each other H, (C1-C10)alkyl,     cycloalkyl, aryl, or a polar group A selected from halogen, epoxy,     —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂N₁₃, phosphate     groups, phosphonate groups, sulfonate groups, sulfonyl groups,     sulfonamides, polyhydroxy, a 4- to 7-membered heteroaryl or     heterocycloalkyl having 1 to 4 ring atoms selected from N, O, S,     wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each     other H, (C1-C10)alkyl, aryl, or heteroaryl, or combinations thereof     such as —(C1-C10)alkylaryl, —(C1-C10)alkyl-cycloalkyl, or one of     —(C1-C10)alkyl, cycloalkyl, aryl substituted by at least one polar     group A, with the proviso that at least one of groups R^(b) and     R^(c) is a polar group A, -   L₁, L₂ represent independently of each other a covalent bond or     —(CH₂)_(p)—, wherein p is 1, 2 or 3, and -   R₅ is H or (C1-C6)alkyl, benzyl or aryl.

Preferably, the substituents at the 3- and 4-position of the β-lactam ring are in trans configuration to each other.

Preferably, X is ortho to the β-lactam ring;

Preferably, Y is meta to the β-lactam and Z is para, or Y is para and Z is meta.

In one embodiment Z is H and Y is preferably —F in para position. In another embodiment Z is a polar group A, preferably a polar group A2 and Y is preferably —H or —F.

In a further aspect the present invention relates to methods of preparation of the compounds of the invention.

In one embodiment the precursor in the synthesis of the compounds of the invention was synthesized according the synthetic route shown in scheme 1.

In another embodiment the precursor in the synthesis of the compounds of the invention was synthesized according the synthetic route shown in scheme 2.

In another embodiment the compounds of the invention were synthesized by coupling a beta-lactam derivative with the precursors described in route A or B as described in Scheme 3, where X is a suitable group for Pd-catalysed C—C bond formation between an aryl group and a terminal alkyne moiety ((i) Sonogashira coupling; (ii) Pd/C, H₂, EtOH).

The final products in scheme 3 were used to synthesize other derivatives by modification of the carboxylic acid moiety. Alternatively, derivatization of the carboxylic acid may be performed before the Sonogashira coupling (i).

It has further been shown that the compounds of the invention display the desired pharmacological activity by evaluation of their potency in vivo (in mice and hamsters). The bioavailability of the compounds of the present invention has been determined by unidirectional Caco2 Permeability measurement.

Thus, the compounds of the invention and their pharmaceutically acceptable acid addition salts, exhibit pharmacological activity and are, therefore, useful as pharmaceuticals. The compounds of the invention have been shown to effectively inhibit cholesterol absorption and are therefore useful in the treatment and/or prevention of atherosclerosis and of the reduction of cholesterol levels.

Thus in yet a further aspect, the present invention is directed to a method of treatment and/or prevention of atherosclerosis, of the reduction of cholesterol levels and of treating or preventing a vascular condition, comprising administering to a mammal in need of such treatment an effective amount of a compound of the present invention.

The novel compounds of the present invention can be used, for example, in the form of pharmaceutical compositions containing a therapeutically effective amount of the active ingredient, if appropriate together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers suitable for enteral, e.g. oral, or parenteral administration. Accordingly, tablets or gelatin capsules are used that contain the active ingredient together with diluents, typically lactose, dextrose, saccharose, mannitol, sorbitol, cellulose and/or lubricants, e.g. diatomaceous earth, talcum, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Tablets may also contain binders, typically magnesium aluminium silicate, starches, typically corn starch, wheat starch, rice starch or arrow root starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, typically starches, agar, alginic acid or a salt thereof, e.g. sodium alginate, and/or effervescent mixtures, or absorbents, colourants, flavourings and sweeteners.

Thus in another aspect, the invention relates to a pharmaceutical composition comprising a compound of the present invention (and optionally other therapeutically effective agents), and a pharmaceutically acceptable carrier for the treatment or prevention of artheriosclerosis or for the reduction of cholesterol levels.

The terms “effective amount” and “therapeutically effective amount” mean that amount of a compound of the present invention (and optionally other therapeutically effective agents), that will elicit a biological or medical response of a tissue, system, animal or mammal, which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing or halting of progression of one or more conditions, for example atherosclerosis, hypercholesterolemia.

The pharmaceutical compositions so obtained which, if desired, contain further pharmacologically active substances, are prepared in a manner known per se by conventional mixing, granulating, sugar-coating, solution or lyophilising methods and contain from about 0.1% to 100%, preferably from about 1% to about 50%, lyophilisate to about 100%, of active ingredient.

The compounds, compositions and treatments of the present invention can be administered by any suitable means which produce contact of these compounds with the site of action in the body, for example in the plasma, liver or small intestine of a mammal or human. Thus the novel compounds of the present invention may also be used in the form of compositions for parenteral, oral, transdermal administration or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspension which, e.g. in the case of lyophilised compositions that contain the active ingredient by itself or together with a carrier, such as mannitol, can be prepared before use. The pharmaceutical compositions can be sterilised and/or can contain excipients, typically preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.

In yet a further aspect, the invention relates to a kit comprising an effective amount of a compound of the present invention in a pharmaceutically acceptable carrier (and optionally an effective amount of another therapeutically effective agent), optionally in separate compartments.

The following non-limiting Examples illustrate the above-described invention in more detail.

EXAMPLES Materials and Methods

Reactions in anhydrous solvents were all performed using oven dried glassware under an atmosphere of N₂. Reagent grade solvents were all purchased from chemical companies and used without prior purification. For chromatographic purification, technical grade solvents were distillated prior to use. TLC was performed using Machery-Nagel Alugram Sil G/UV₂₅₄ TLC plates and visualized with ultraviolet light at 254 nm and CAM, p-anisaldehyde or KMnO₄ staining. Chromatographic purification of products was accomplished by flash chromatography on silica gel 60 (230-400 mesh, 0.04-0.063 mm) from Merck at rt and 0.3-0.5 mbar air pressure or with a Armen Spotflash Automated Purification System and commercial prepacked silica gel cartridges; fractions containing product were pooled, the solvents were evaporated under reduced pressure and the residue was dried under high vacuum to give the product. NMR spectra were recorded on a Varian Mercury 300 MHz apparatus operating at 300 MHz and 75 MHz for ¹H and ¹³C, respectively, and chemical shifts (δ) were referenced to the internal solvent signals. Melting points were measured on a Büchi 510 apparatus in open capillaries and all melting points are uncorrected. IR-Spectra were recorded in CHCl₃ on a Perkin Elmer Spectrum RX I FT-IR apparatus (thin films on NaCl plates) and are reported as absorption maxima in cm⁻¹ (data not submitted). High resolution matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) and electrospray ionization (ESI-MS) were performed by the mass spectrometry service of the LOC at the ETH, Zürich and were recorded in positive ion mode. Analytical LC/MS was performed on a Dionex 3000 UPtimate System. The flow rate was 1 mL/min. Column: Agilent Technologies Eclipse Plus C18 (RP-18, 3.5 μm, 3.0×30 mm). Solvent A: CH₃CN, Solvent B: 0.1% TFA in H₂O. All separations were performed at 35° C.

Example 1 2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetic acid

t_(R)=2.99 min, [M+H]+=552.3;

(a) Synthesis of benzyl 2-(3-ethynyloxetan-3-yloxy)acetate

To a solution of TMS-acetylene (5.12 mL) in THF (20 mL) at −78° C. was added n-BuLi (1.6M in hexanes, 21.1 mL). The reaction was stirred at −78° C. for 20 min and a solution of oxetane-3-one (2 g) in THF (2 mL) was added. The reaction mixture was stirred at −78° C. for an additional 30 min and an aliquot was evaporated (white solid). The reaction mixture was evaporated to give a foam that was used in the next reactions.

To a suspension of sodium hydride (60% suspension, 117 mg) in DMF (2 mL) was added the above alcohol (400 mg, in 1.5 mL DMF). The reaction mixture was stirred at RT for 2 h and ethyl bromoacetate (0.52 mL) was added. The reaction mixture was stirred at RT for 1 h, followed by addition of sat. aq. NH₄Cl and extraction with ethyl acetate. After evaporation the residue was purified by flash chromatography to afford a mixture of TMS-protected (200 mg) and TMS-deprotected (113 mg) alkynes as colourless oil. The former could be transformed into the later by treatment of the mixture with TBAF in THF (typically 80% yield).

(b) Synthesis of 2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetic acid

Pd(PPh₃)₄ (0.15 eq.), CuI (0.30 eq.), TBAI (2.5 eq.), triflate (0.66 g) and benzyl 2-(3-ethynyloxetan-3-yloxy)acetate (0.44 g, 1.5 eq.) were placed in a flask and dissolved in acetonitrile. Triethylamine (6 eq.) was added under N₂ and the reaction mixture was stirred at 30° C. for 16 h.

The reaction was quenched by addition of sat. aq. NH₄Cl and extracted with EtOAc. The combined organic extracts were combined and evaporated. The residue was dry-loaded on FC to give the coupling product as a colourless oil (0.61 g). The oil was placed in a flask with Pd/C (10%, 100 mg) and EtOH (10 mL) and atmosphere was replaced with H₂. Stirring under H₂ atmosphere (1 atm) for 3 h, followed by filtration through a pad of celite and evaporation of the solvent afforded 2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetic acid as a white foam (0.49 g).

Example 2 Synthesis of 2-(3-((3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenyl)propyl)(methyl)amino)oxetan-3-yl)acetic acid (a) Synthesis of benzyl 2-(3-(methyl (prop-2-ynyl)amino)oxetan-3-yl)acetate

A mixture of N-methyl-propargylamine (0.27 g) and benzyl 2-(oxetan-3-ylidene)acetate (0.41 g) was stirred neat at RT for 12 h. The excess amine was removed by evaporation to give benzyl 2-(3-(methyl(prop-2-ynyl)amino)oxetan-3-yl)acetate quantitatively (0.54 g).

(b) Synthesis of 2-(3-((3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenyl)propyl)(methyl)amino)oxetan-3-yl)acetic acid

The reaction between the above triflate (0.5 g) and benzyl 2-(3-(methyl(prop-2-ynyl)amino)oxetan-3-yl)acetate (1.5 eq.) obtained in step (a) under the coupling conditions described in Example 1 afforded, after Sonogashira coupling and hydrogenation, 2-(3-((3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenyl)propyl)(methyl)amino)oxetan-3-yl)acetic acid as a white foam (0.32 g).

Example 3 (R)-2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-3-phenylpropanoic acid

t_(R)=3.43 min, [M+H]+=700.0;

Example 4 2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-3-(4-hydroxyphenyl)-2-methylpropanoic acid

t_(R)=3.02 min, [M−4H+Na]+=747.0;

Example 5 3-cyclohexyl-2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)propanoic acid

t_(R)=3.60 min, [M+H₂O]+=721.6;

Example 6 (R)-2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-2-phenylacetic acid

t_(R)=3.49 min, [M+H]⁺=685.0;

Example 7 (R)-2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-2-(4-hydroxyphenyl)acetic acid

t_(R)=2.98 min, [M+H]+=701.2;

Example 8 1-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetyl)piperidine-3-carboxylic acid

t_(R)=3.15 min, [M+H]+=663.2;

Example 9 1-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetyl)piperidine-4-carboxylic acid

t_(R)=2.89 min, [M+H]+=663.2;

Example 10 3-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-4-methylpentanoic acid

t_(R)=3.25 min, [M−2H+K]+=701.0;

Example 11 2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)-N-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)acetamide

t_(R)=2.71 min, [M+H]+=729.0;

Example 12 N-(2-(dimethylamino)ethyl)-2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamide

t_(R)=2.23 min, [M+H]+=622.1;

Example 13 2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-N,N,N-trimethylethanaminium iodide

t_(R)=2.21 min, [M]-1-=636.1;

Example 14 2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)-N-(2-morpholinoethyl)acetamide

t_(R)=2.28 min, [M+H]+=664.1;

Example 15 4-(2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)ethyl)-4-methylmorpholin-4-ium iodide

t_(R)=2.26 min, [M+H]+=678.1;

Example 16 3-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)benzoic acid

t_(R)=2.95 min, [M+NH₄]+=689.1;

Example 17 4-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)benzoic acid

t_(R)=2.92 min, [M+NH₄]+=689.1;

Example 18 2-((3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)methyl)oxazole-4-carboxylic acid

t_(R)=3.35 min, [M−H+H₂O]+=631.8;

Example 19 (R)-1-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetyl)pyrrolidine-2-carboxylic acid

t_(R)=3.12 min, [M+H]+=649.1;

Example 20 (S)-1-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetyl)pyrrolidine-2-carboxylic acid

t_(R)=2.96 min, [M+H]+=649.1;

Example 21 (3R,4S)-4-(4-(2-(3-(2-((S)-2-(1H-tetrazol-5-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)azetidin-2-one

t_(R)=2.97 min, [M+H]+=673.1;

Example 22 (R)-1-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetyl)pyrrolidine-2-carboxamide

t_(R)=2.83 min, [M+H]+=647.7;

Example 23 1-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetyl)piperidine-2-carboxylic acid

t_(R)=3.10 min, [M+H]+=663.1;

Example 24 (R)-2-(2-(3-((3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenyl)propyl)(methyl)amino)oxetan-3-yl)acetamido)-3-methylbutanoic acid

t_(R)=3.29 min, [M+H]+=678.1;

Example 25 (R)-2-(2-(3-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenyl)propylamino)oxetan-3-yl)acetamido)-3-methylbutanoic acid

t_(R)=2.79 min, [M+H]+=664.1;

Example 26 (R)-2-(2-(3-(3-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-3-methylbutanoic acid

t_(R)=3.02 min, [M+NH₄]+=669.1;

Example 27 (S)-2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-3-methylbutanoic acid

t_(R)=3.14 min, [M+H]+=651.1;

Example 28 2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)ethanesulfonic acid

t_(R)=2.58 min, [M−H]+NH₄+=677.1;

Example 29 (2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)methanesulfonic acid

t_(R)=3.46 min, [M−H+NH₄]+=661.2;

Example 30 1-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-2-methylpropylphosphonic acid

t_(R)=2.64 min, [M+Na]+=709.0;

Example 31 (2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)methylphosphonic acid

t_(R)=2.70 min, [M+Na]+=667.1;

Example 32 2,2′-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetylazanediyl)diacetic acid

t_(R)=2.70 min, [M+H]+=667.1;

Example 33 (R)-2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)succinic acid

t_(R)=3.29 min, [M+H]+=667.0;

Example 34 (R)-2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-3-hydroxypropanoic acid

t_(R)=2.83 min, [M+H]+=639.2;

Example 35 1-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)cyclobutanecarboxylic acid

t_(R)=3.11 min, [M+H]⁺=649.2;

Example 36 1-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)cyclopentanecarboxylic acid

t_(R)=3.15 min, [M+H]⁺=662.9;

Example 37 2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-2-methylpropanoic acid

t_(R)=3.19 min, [M+H]+=638.1

Example 38 2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamide

t_(R)=2.68 min, [M−H+NH₄]+=567.0;

Example 39 (R)-2-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-3-methylbutanoic acid

t_(R)=3.28 min, [M+H]+=651.1;

Example 40 (R)-1-(2-(3-(4-((2S,3R)-3-(2-(4-fluorophenoxy)ethyl)-1-(4-fluorophenyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetyl)pyrrolidine-2-carboxylic acid

t_(R)=3.23 min, [M+H]+=635.1;

Example 41 (R)-1-(2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-oxopropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetyl)pyrrolidine-2-carboxylic acid

t_(R)=3.16 min, [M+H]+=647.1;

Example 42 (R)-2-(2-(3-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)propyl)phenyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-3-methylbutanoic acid

Example 43 (R)-2-(2-(3-(4-((2S,3R)-1-(4-(3-(1H-1,2,4-triazol-1-yl)propyl)phenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-3-methylbutanoic acid

Example 44 (R)-2-(2-(3-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxo-1-(4-(3-(pyridin-2-ylamino)propyl)phenyl)azetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-3-methylbutanoic acid

Example 45 (R)-2-(2-(3-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(oxazol-2-ylamino)propyl)phenyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamido)-3-methylbutanoic acid

Example 46 N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(3-(4-((2S,3R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-oxoazetidin-2-yl)phenethyl)oxetan-3-yloxy)acetamide

t_(R)=2.89 min, [M+H]+=655.1;

Example 47 Accute Cholesterol Absorption Inhibition Assay in Mice

Compounds were added to a solution of 0.5% Methylcellulose (Sigma)/5% Solutol, BASF) or another suitable vehicle at a concentration of 0.1-1 mg/ml. C56BL/6 mice (n=3-6/group), aged 6-8 weeks were dosed orally with 0.1 ml of vehicle or 0.1 mL of vehicle containing the test compound (0.5-5 mg/kg) or ezetimibe (10 mg/kg) as positive control. Thirty minutes later all of the mice were dosed orally with 0.1 mL corn oil containing 2 μCi [³H]-cholesterol per mouse. Two hours after administration of radiolabeled cholesterol, the animals were euthanized and blood collected. Cholesterol counts in plasma were determined, and percent inhibition of cholesterol absorption was calculated relative to the vehicle control.

TABLE 1 Efficacy in mice: representative examples Cholesterol Absorption Compound Dose Inhibition (%) Example 1  1 mg/kg 87 Example 19  1 mg/kg 83 Example 20  1 mg/kg 42 Example 22  1 mg/kg 80 Example 23  1 mg/kg 73 Example 28  1 mg/kg 63 Example 39  1 mg/kg 82 Ezetimibe 10 mg/kg 87

Example 48 Long-Term LDL Lowering in Syrian Golden Hamsters

Groups of 6 male hamsters weighing 90±10 g are fed a high fat diet (g/100 g: corn oil, 5; coconut oil, 5; cholesterol, 0.2; standard chow, 89.8) for 7 days. Afterwards vehicle or test compounds (3-10 mg/kg bw/day) in a solution of 0.5% Methylcellulose, 5% Solutol or another suitable vehicle are administered at least three times daily for 14 consecutive days. Following an overnight fasting period, blood serum is obtained from the retro-orbital sinus of each animal on day 0 (7 days after initiating of the high fat diet) and on days 8 and 15 after dosing for 7 and 14 days. The serum is assayed for total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides. The percent change of treated relative to the vehicle control group is determined.

TABLE 2 Efficacy in Hamster: representative examples Dose LDL reduction Compound (mg/kg/day) @ day 14 (%) Example 34 3 × 1 76 Example 35 3 × 1 80 Example 39 3 × 1 74 Example 46 3 × 1 67

Example 49 Determination of Absorption

The permeability of the compounds of the present invention was determined using the Cloe Screen® (unidirectional Cloe Screen MDR1-MDCK permeability assay; Cyprotex) and is expressed by P_(app) (cm·s⁻¹). Caco-2 cells are widely used as an in vitro model for predicting human drug absorption. The Caco-2 cell line is derived from a human colorectal carcinoma, and when cultured, the cells spontaneously differentiate into monolayers of polarised enterocytes. The cells are typically seeded on Transwell™ plates and form a confluent monolayer over 20 days prior to the experiment. On day 20, the test compound is added to the apical side of the membrane and the transport of the compound across the monolayer is monitored over a 2 hour time period. The permeability coefficient (P_(app)) is calculated from the equation: P_(app)=(dQ/dt)/(C₀xA), where (dQ/dt) is the rate of permeation of the drug across the cells, C₀ is the donor compartment concentration at time zero and A is the area of the cell monolayer.

TABLE 3 Impermeability: representative examples Compound P_(app) in cm · s⁻¹ Example 1 1.68 × 10⁻⁶ Example 19 0.14 × 10⁻⁶ Example 34 0.57 × 10⁻⁶ Example 35 0.73 × 10⁻⁶ Example 39 0.92 × 10⁻⁶ Example 46 1.09 × 10⁻⁶ Ezetimibe   46 × 10⁻⁶ 

The invention claimed is:
 1. A compound according to formula I or a pharmaceutically acceptable salt thereof,

wherein W, X and Y represent, independently of each other, H, —(C1-C10)alkyl, —OH, —O(C1-C10)alkyl, -aryl, halogen, —CF₃; Z represents H, —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, aryl, a polar group A, or combinations thereof, wherein the —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, or aryl, may be substituted by at least one polar group A, wherein A is selected from halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂R₁₃, phosphate groups, phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered heteroaryl or 4- to 7-membered heterocycloalkyl each having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H, (C1-C10)alkyl, aryl or heteroaryl; V represents —CH₂—, —CH(OH)—, —C(═O)—, —O—, NR₄, —C(CH₂OCH₂)— wherein R₄ represents H, (C1-C10)alkyl or aryl; S is a group of formula IIIa or IIIb

wherein B₂ represents —C(O)NR^(d)—, —C(O)O—, aryl or heteroaryl; R₅ is H or (C1-C6)alkyl; R^(a), R^(d) represent (i) independently of each other H, (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂R₁₃, phosphate groups, phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered heteroaryl or 4- to 7-membered heterocycloalkyl each having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl, or (ii) R^(a) and R^(d) form together a N-containing 5- or 6-membered heteroaryl or heterocycloalkyl; L₁, L₂ represent independently of each other a covalent bond, a 5- or 6-membered arylgroup or a group —(CH₂)_(p)—, wherein p is 1, 2 or 3; R^(b), R^(c) represent (i) independently of each other H, (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂R₁₃, phosphate groups, phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered heteroaryl or 4- to 7-membered heterocycloalkyl each having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl, or (ii) R^(b) and R^(c) form together a (C3-C6)cycloalkyl or (C3-6)heterocycloalkyl, and m is 0, 1 or 2; with the proviso that at least one of groups R^(a), R^(b), R_(c), R^(d) is a polar group A.
 2. The compound according to claim 1 wherein V is CH(OH), —C(═O)— or —O— and/or wherein W, X, Y and Z independently represent H, halogen, or —OH.
 3. The compound according to claim 1 wherein Z is H and Y is —F in para position.
 4. The compound according to claim 1, wherein B₂ represents —C(O)NR^(d)—, —C(O)O—, or a five-membered heteroaryl having two heteroatoms selected from N, O or S.
 5. The compound according to claim 1 having the formula VIa, VIb, VIc or formula VIIa, VIIb, VIIc or a pharmaceutically acceptable salt thereof,

wherein X, Y are, independently of each other, H, OH or F; Z represents H, —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, aryl, a polar group A, or combinations thereof, wherein the —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, or aryl, may be substituted by at least one polar group A, wherein A is selected from halogen, epoxy, —COR₆, —COORS, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂R₁₃, phosphate groups, phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered heteroaryl or 4- to 7-membered heterocycloalkyl each having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl; Q is —O—, —NR₅—, —S—, m is 0, 1 or 2; L₁, L₂ represent independently of each other a covalent bond, a 5- or 6-membered arylgroup or a group —(CH₂)_(p)—, wherein p is 1, 2 or 3; R₅ is H, (C1-C6)alkyl, benzyl or aryl; R^(a), R^(d) represent (i) independently of each other H, (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂R₁₃, phosphate groups, phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered heteroaryl or 4- to 7-membered heterocycloalkyl each having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl, or (ii) R^(a) and R^(d) form together a N-containing 5- or 6-membered heteroaryl or heterocycloalkyl; R^(b), R^(c) represent (i) independently of each other H, (C1-C10)alkyl, cycloalkyl, aryl, a polar group A, or combinations thereof, wherein A is selected from halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂R₁₃, phosphate groups, phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered heteroaryl or 4- to 7-membered heterocycloalkyl each having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl, or (ii) R^(b) and R^(c) form together a (C3-C6)cycloalkyl or (C3-6)heterocycloalkyl; with the proviso that at least one of groups R^(a), R^(b), R^(c), R^(d) is a polar group A.
 6. The compound according to claim 1 wherein (i) L₁ is —(CH₂)_(p)—, wherein p is 1, 2 or 3 and L₂ is a covalent bond, or (ii) L₁ is a covalent bond and L₂ is a 5- or 6-membered aryl group.
 7. The compound according to claim 1 having formula VIIIa or VIIIb

wherein X, Y are independently of each other, H, OH or F; Z represents H, —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, aryl, a polar group A, or combinations thereof, wherein the —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, or aryl, may be substituted by at least one polar group A, wherein A is selected from halogen, epoxy, —COR₆, —COOR₇, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂R₁₃, phosphate groups, phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered heteroaryl or 4- to 7-membered heterocycloalkyl each having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl; R^(b), R^(c) represent independently of each other H, (C1-C10)alkyl, cycloalkyl, aryl, or a polar group A selected from halogen, epoxy, —COR₆, —COOR₆, —NR₈R₉, —N⁺R₈R₉R₁₀, —OR₁₁, —CONR₁₂R₁₃, phosphate groups, phosphonate groups, sulfonate groups, sulfonyl groups, sulfonamides, polyhydroxy, a 4- to 7-membered heteroaryl or 4- to 7-membered heterocycloalkyl each having 1 to 4 ring atoms selected from N, O, S, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ are independently of each other H, (C1-C10)alkyl, aryl, or heteroaryl, L₁, L₂ represent independently of each other a covalent bond or —(CH₂)_(p)—, wherein p is 1, 2 or 3, and R₅ is H or (C1-C6)alkyl, benzyl or aryl.
 8. The compound according to claim 1 wherein R^(b) and R^(c) are a C3- or C4-cycloalkyl or an oxetane.
 9. The compound according to claim 1 wherein the substituents at the 3- and 4-position of the β-lactam ring are in trans configuration to each other.
 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 with a pharmaceutically acceptable carrier, optionally further comprising one or more additional active agents.
 11. A method for treating or reducing the risk of developing arthrosclerosis or for the reduction of cholesterol levels comprising administering to a subject in need of such treatment an effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim
 10. 12. The compound according to claim 1, wherein Z is —(C1-C10)alkyl, —(C1-C10)alkenyl, —(C1-C10)alkynyl, or aryl, substituted by at least one polar group A. 